tbuckley/cabot-search huggingface dataset:
Early evaluation of the safety, reactogenicity, and immune response after a single dose of modified vaccinia Ankara–Bavaria Nordic vaccine against mpox in children: a national outbreak response
Authors: Shamez N Ladhani, Alexander C Dowell, Scott Jones, Bethany Hicks, Cathy Rowe, Jusnara Begum, Dagmar Wailblinger, John Wright, Stephen Owens, Ailsa Pickering, Benjamin Shilltoe, Paddy McMaster, Elizabeth Whittaker, Jianmin Zuo, Annabel Powell, Gayatri Amirthalingam, Sema Mandal, Jamie Lopez-Bernal, Mary E Ramsay, Neave Kissane, Michael Bell, Heather Watson, David Ho, Bassam Hallis, Ashley Otter, Paul Moss, Jonathan Cohen
Journal: The Lancet Infectious Diseases (2023)

In response to a national mpox (formerly known as monkeypox) outbreak in England, children exposed to a confirmed mpox case were offered modified vaccinia Ankara-Bavaria Nordic (MVA-BN), a third-generation smallpox vaccine, for post-exposure prophylaxis. We aimed to assess the safety and reactogenicity and humoral and cellular immune response, following the first reported use of MVA-BN in children.
Endoscopic screening of the upper gastrointestinal tract for second primary tumors in patients with head and neck cancer in a Western country
Authors: Laurelle van Tilburg, Steffi E. M. van de Ven, Pieter Jan F. de Jonge, Wilmar de Graaf, Manon C. W. Spaander, Suzan Nikkessen, Jose A. Hardillo, Aniel Sewnaik, Dominiek A. Monserez, Hetty Mast, Stijn Keereweer, Marco J. Bruno, Robert J. Baatenburg de Jong, Arjun D. Koch
Journal: Endoscopy (2023)

Patients with head and neck squamous cell carcinoma (HNSCC) can develop second primary tumors (SPTs) in the esophagus. Endoscopic screening could lead to detection of SPTs at early stages and improve survival.We performed a prospective endoscopic screening study in patients with curably treated HNSCC diagnosed between January 2017-July 2021 in a Western country. Screening was performed synchronously (< 6 months) or metachronously (≥ 6 months) after HNSCC diagnosis. Routine imaging for HNSCC consisted of flexible transnasal endoscopy with positron emission tomography/computed tomography or magnetic resonance imaging, depending on primary HNSCC location. The primary outcome was prevalence of SPTs, defined as presence of esophageal high grade dysplasia or squamous cell carcinoma.202 patients (mean age 65 years, 80.7 % male) underwent 250 screening endoscopies. HNSCC was located in the oropharynx (31.9 %), hypopharynx (26.9 %), larynx (22.2 %), and oral cavity (18.5 %). Endoscopic screening was performed within 6 months (34.0 %), 6 months to 1 year (8.0 %), 1-2 years (33.6 %), and 2-5 years (24.4 %) after HNSCC diagnosis. We detected 11 SPTs in 10 patients (5.0 %, 95 %CI 2.4 %-8.9 %) during synchronous (6/85) and metachronous (5/165) screening. Most patients had early stage SPTs (90 %) and were treated with curative intent with endoscopic resection (80 %). No SPTs in screened patients were detected with routine imaging for HNSCC before endoscopic screening.In 5 % of patients with HNSCC, an SPT was detected with endoscopic screening. Endoscopic screening should be considered in selected HNSCC patients to detect early stage SPTs, based on highest SPT risk and life expectancy according to HNSCC and comorbidities.
Unloading potatoes: Potato breeding moves forward with only half the genome
Authors: Husain I. Agha, Laura M. Shannon, Peter L. Morrell
Journal: Cell Genomics (2023)

Potato is one of the most important food crops in the world and, in contrast to other staples, has not seen large improvements in yield. Agha, Shannon, and Morrell preview an article recently published in Cell, "Phylogenomic discovery of deleterious mutations facilitates hybrid potato breeding," which advances potato breeding strategies via a genetic approach.
A highly selective humanized DDR1 mAb reverses immune exclusion by disrupting collagen fiber alignment in breast cancer
Authors: Junquan Liu, Huai-Chin Chiang, Wei Xiong, Victor Laurent, Samuel C Griffiths, Jasmin Dülfer, Hui Deng, Xiujie Sun, Y Whitney Yin, Wenliang Li, Laurent P Audoly, Zhiqiang An, Thomas Schürpf, Rong Li, Ningyan Zhang
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background Immune exclusion (IE) where tumors deter the infiltration of immune cells into the tumor microenvironment has emerged as a key mechanism underlying immunotherapy resistance. We recently reported a novel role of discoidin domain-containing receptor 1 (DDR1) in promoting IE in breast cancer and validated its critical role in IE using neutralizing rabbit monoclonal antibodies (mAbs) in multiple mouse tumor models. Methods To develop a DDR1-targeting mAb as a potential cancer therapeutic, we humanized mAb9 with a complementarity-determining region grafting strategy. The humanized antibody named PRTH-101 is currently being tested in a Phase 1 clinical trial. We determined the binding epitope of PRTH-101 from the crystal structure of the complex between DDR1 extracellular domain (ECD) and the PRTH-101 Fab fragment with 3.15 Å resolution. We revealed the underlying mechanisms of action of PRTH-101 using both cell culture assays and in vivo study in a mouse tumor model. Results PRTH-101 has subnanomolar affinity to DDR1 and potent antitumor efficacy similar to the parental rabbit mAb after humanization. Structural information illustrated that PRTH-101 interacts with the discoidin (DS)-like domain, but not the collagen-binding DS domain of DDR1. Mechanistically, we showed that PRTH-101 inhibited DDR1 phosphorylation, decreased collagen-mediated cell attachment, and significantly blocked DDR1 shedding from the cell surface. Treatment of tumor-bearing mice with PRTH-101 in vivo disrupted collagen fiber alignment (a physical barrier) in the tumor extracellular matrix (ECM) and enhanced CD8 + T cell infiltration in tumors. Conclusions This study not only paves a pathway for the development of PRTH-101 as a cancer therapeutic, but also sheds light on a new therapeutic strategy to modulate collagen alignment in the tumor ECM for enhancing antitumor immunity.
Are we measuring what matters to older people?
Authors: Simon P Conroy, James D van Oppen
Journal: The Lancet Healthy Longevity (2023)

Comprehensive geriatric assessment is the core toolkit of geriatric medicine. Awareness of and engagement in comprehensive geriatric assessment are crucial competences for all professionals caring for older people living with frailty. The fundamental tenet of comprehensive geriatric assessment is person centredness, which means orienting problem evaluation and intervention plans around an individual's specific biopsychosocial situation to maximise their function and participation. Person-centred outcomes are frequently neglected from measurements of health-care delivery, service improvement, and research. Instead, systems tend to measure outcomes of the health-care service (ie, resource use) or a person's destination following a health-care process. The absence of person-centred outcome measures risks the delivery of health care that seeks to achieve, and is benchmarked against, outcomes that are not best for the patient. We must, therefore, ensure that the outcomes that matter to older people are being measured.
Molecular mechanisms of snoRNA-IL-15 crosstalk in adipocyte lipolysis and NK cell rejuvenation
Authors: Yaohua Zhang, Zilong Zhao, Lisa A. Huang, Yuan Liu, Jun Yao, Chengcao Sun, Yajuan Li, Zhao Zhang, Youqiong Ye, Fei Yuan, Tina K. Nguyen, Nikhil Reddy Garlapati, Andrew Wu, Sergey D. Egranov, Abigail S. Caudle, Aysegul A. Sahin, Bora Lim, Laura Beretta, George A. Calin, Dihua Yu, Mien-Chie Hung, Michael A. Curran, Katayoun Rezvani, Boyi Gan, Zhi Tan, Leng Han, Chunru Lin, Liuqing Yang
Journal: Cell Metabolism (2023)

Obesity, in which the functional importance of small nucleolar RNAs (snoRNAs) remains elusive, correlates with risk for many cancer types. Here, we identify that the serum copies of adipocyte-expressed SNORD46 correlate with body mass index (BMI), and serum SNORD46 antagonizes interleukin-15 (IL-15) signaling. Mechanically, SNORD46 binds IL-15 via G11, and G11A (a mutation that significantly enhances binding affinity) knockin drives obesity in mice. Functionally, SNORD46 blocks IL-15-induced, FER kinase-dependent phosphorylation of platelet glycoprotein 4 (CD36) and monoglyceride lipase (MGLL) in adipocytes, leading to inhibited lipolysis and browning. In natural killer (NK) cells, SNORD46 suppresses the IL-15-dependent autophagy, leading to reduced viability of obese NK. SNORD46 power inhibitors exhibit anti-obesity effects, concurring with improved viability of obese NK and anti-tumor immunity of CAR-NK cell therapy. Hence, our findings demonstrate the functional importance of snoRNAs in obesity and the utility of snoRNA power inhibitors for antagonizing obesity-associated immune resistance.
Preclinical characterization of WB737, a potent and selective STAT3 inhibitor, in natural killer/T‐cell lymphoma
Authors: Yali Wang, Wenbo Zhou, Jianfeng Chen, Jinghong Chen, Peng Deng, Huang Chen, Yichen Sun, Zhaoliang Yu, Diwen Pang, Lizhen Liu, Peili Wang, Jing Han Hong, Bin Tean Teh, Huiqiang Huang, Wenyu Li, Zhengfang Yi, Soon Thye Lim, Yihua Chen, Choon Kiat Ong, Mingyao Liu, Jing Tan
Journal: MedComm (2023)

Natural killer/T-cell lymphoma (NKTL) is an uncommon malignancy with poor prognosis and limited therapeutic options. Activating mutations of signal transducer and activator of transcription 3 (STAT3) are frequently found in patients with NKTL, suggesting that targeted inhibition of STAT3 is a potential therapeutic option for this disease. Here, we have developed a small molecule drug WB737 as a novel and potent STAT3 inhibitor that directly binds to the STAT3-Src homology 2 domain with high affinity. In addition, the binding affinity of WB737 to STAT3 is 250-fold higher than STAT1 and STAT2. Interestingly, WB737 is more selective for NKTL with
Targeting PCSK9 to tackle cardiovascular disease
Authors: Sandra Hummelgaard, Joachim Pold Vilstrup, Camilla Gustafsen, Simon Glerup, Kathrin Weyer
Journal: Pharmacology & Therapeutics (2023)

Lowering blood cholesterol levels efficiently reduces the risk of developing atherosclerotic cardiovascular disease (ASCVD), including coronary artery disease (CAD), which is the main cause of death worldwide. CAD is caused by plaque formation, comprising cholesterol deposits in the coronary arteries. Proprotein convertase subtilisin kexin/type 9 (PCSK9) was discovered in the early 2000s and later identified as a key regulator of cholesterol metabolism. PCSK9 induces lysosomal degradation of the low-density lipoprotein (LDL) receptor in the liver, which is responsible for clearing LDL-cholesterol (LDL-C) from the circulation. Accordingly, gain-of-function PCSK9 mutations are causative of familial hypercholesterolemia, a severe condition with extremely high plasma cholesterol levels and increased ASCVD risk, whereas loss-of-function PCSK9 mutations are associated with very low LDL-C levels and protection against CAD. Since the discovery of PCSK9, extensive investigations in developing PCSK9 targeting therapies have been performed. The combined delineation of clear biology, genetic risk variants, and PCSK9 crystal structures have been major drivers in developing antagonistic molecules. Today, two antibody-based PCSK9 inhibitors have successfully progressed to clinical application and shown to be effective in reducing cholesterol levels and mitigating the risk of ASCVD events, including myocardial infarction, stroke, and death, without any major adverse effects. A third siRNA-based inhibitor has been FDA-approved but awaits cardiovascular outcome data. In this review, we outline the PCSK9 biology, focusing on the structure and nonsynonymous mutations reported in the PCSK9 gene and elaborate on PCSK9-lowering strategies under development. Finally, we discuss future perspectives with PCSK9 inhibition in other severe disorders beyond cardiovascular disease.
Non-pharmacological and melatonin interventions for pediatric sleep initiation and maintenance problems: A systematic review and network meta-analysis
Authors: Samantha Mombelli, Valeria Bacaro, Sara Curati, Francesca Berra, Marco Sforza, Vincenza Castronovo, Luigi Ferini-Strambi, Andrea Galbiati, Chiara Baglioni
Journal: Sleep Medicine Reviews (2023)
Abstract 15060: New Diagnostic Method Using Latest Spectral Computed Tomography With Dual-Layer Detector to Diagnose Pulmonary Thromboembolism and Pulmonary Infarcted Tissue Changes
Authors: Nobusada Funabashi, Kazuo Misumi
Journal: Circulation (2022)

Introduction: Spectral CT with a dual-layer detector generates CT images at any keV (range: 40-200) after ordinary acquisition using virtual monoenergetic settings (VMS). An appropriate keV improves the contrast of a pulmonary artery (PA) thrombus (PAT). On iodine no water (INW) display, areas with decreased PA blood flow are visualized. With effective atomic number display (Z effective), infarcted and normal lung tissues are distinguished. Hypothesis: Spectral CT improves the detection of PAT, areas with decreased PA blood flow, and infarcted lung tissue, increasing diagnostic accuracy. Methods: We performed enhanced 128 slice Spectral CT 7500 (Philips) scans with a dual-layer detector in 23 patients (11 males, 61±13 years) with clinically suspected PAT. VMS images at various keV values were created from spectral-based images. We developed an INW display to detect decrements in PA blood flow and also made Z effective displays to distinguish infarcted from normal lung tissue. We measured patent PA lumens, PAT, lung areas with decrements in PA flow and infarcted lung tissue. Results: 19 patients had PAT. Of the remaining 4 patients, two revealed decrements in PA flow on INW display and lung tissue changes on Z effective display. On a spectral profile analysis using images in the early phases using contrast, lower keV values were associated with markedly and slightly increased mean CT values for the patent PA lumen and PAT, respectively. Lower keV values were associated with markedly increased mean CT values for normal lung tissue, however, mean CT values were constant at various keV values for an area related to decrements in PA blood flow by INW display and also infarcted lung tissue by Z profile, simultaneously, respectively (Figure). Conclusions: A small PAT may be missed in enhanced CT. However, spectral CT can detect PAT, an area corresponding to decrements in PA blood flow on INW display, and also distinguish infarcted from normal lung tissue on a Z profile, simultaneously.
Abstract 15122: Escalation Strategies, Management, and Outcomes of Acute Myocardial Infarction-Cardiogenic Shock Patients Receiving Percutaneous Left Ventricular Support
Authors: Sri H Patlolla, Saraschandra Vallabhajosyula
Journal: Circulation (2022)

Introduction: Despite well-established device selection algorithms, there remain wide variations in mechanical circulatory support (MCS) device utilization in patients with cardiogenic shock complicating acute myocardial infarction (AMI-CS). Further, there are limited national-level data on the contemporary practices of MCS device use. Methods: To evaluate national utilization patterns of MCS devices, we identified adult admissions (&gt;18 years) with AMI-CS from the HCUP-NIS data (2005-2017). Use of MCS devices including intraaortic balloon pump (IABP), percutaneous left ventricular assist devices (pLVAD) (Impella/Tandem Heart), and extracorporeal membrane oxygenation (ECMO) during hospitalization was identified. We evaluated trends in the initial MCS device used (IABP alone, pLVAD alone, or ≥2 MCS devices), device escalation, bridging to durable LVAD/heart transplantation, and predictors of in-hospital mortality and device escalation. Results: Among a total of 327,283 AMI-CS admissions in this 13-year period, 132,146 (40.2%) had an MCS device with information on timing of placement. IABP, pLVAD, ≥2 MCS, and ECMO devices were used as initial device in 120,928 (92.0%), 8,202 (6.2%), 2,305 (1.7%), and 711 (0.1%) admissions, respectively. Most admissions were maintained on initiated MCS device with 1-1.5% being escalated (IABP to pLVAD/ECMO, pLVAD to ECMO). The median time to escalation across all devices categories was 2 (IQR 1-4) days. Urban, medium, and large-sized hospitals, and acute multiorgan failure were significant independent predictors of MCS escalation. In admissions receiving MCS, escalation of MCS device was associated with higher in-hospital mortality (adjusted OR 1.56, 95% CI 1.38-1.75; p &lt;0.001). Admissions receiving durable LVAD/heart transplantation increased over time in those initiated on pLVAD and ≥2 MCS devices resulting in lower in-hospital mortality. Conclusions: In this 13-year study, escalation from initial MCS device was associated with higher in-hospital mortality suggestive of higher acuity of illness. However, the observed increase in number of durable LVADs or heart transplantations may be an indication of the utility of these MCS devices as successful bridge therapies.
Abstract 15086: Impact of Vegan Meal Kits on Cardiometabolic Endpoints: A Randomized, Controlled Clinical Trial
Authors: Kevin Pham, Joseph SKY, Robert Hill, Andrew Haynes, Sahra Pak, Sachin A Shah
Journal: Circulation (2022)

Background: While vegan diets have shown cardiometabolic health benefits, implementing such diets can pose a practical challenge. Boxed meal delivery kits have emerged in the market to meet this gap. We evaluated the impact of a vegan boxed meal kit (VBK) compared to a standard omnivorous boxed meal kit (OBK) on cardiometabolic endpoints. Methods: This was a randomized, controlled, parallel-designed trial. Overweight (BMI ≥25 kg/m 2 ) military beneficiaries on a standard omnivorous diet were randomized to consume a VBK or OBK for 4 weeks. The meal kits provided lunch and dinner. The primary endpoint was change from baseline at 4 weeks in calculated low-density lipoproteins (LDL-c). Other lipid parameters and weight were also evaluated. Results: A total of 54 participants (38.8±11.6 years) completed the VBK (N=27) and OBK (N=27) groups. Baseline LDL-c in VBK and OBK groups were 109.7±34.2 mg/dL and 101.0±34.1 mg/dL respectively. Baseline weight in VBK and OBK groups were 202.8±39.9 pounds and 197.6±46.4 pounds respectively. LDL-c changed from baseline in the VBK and OBK groups by -10.0±19.3% and +1.0±15.0%, respectively (p=0.028). Weight changed from baseline in the VBK and OBK by -2.7±2.1% and -0.39±1.69%, respectively (p&lt;0.001). Total cholesterol was significantly lower in the VBK, while no differences were seen in HDL and TG. Dietary compliance was excellent. Conclusion: Vegan boxed meal kits significantly reduced LDL-c and weight in a 4-week period, and may serve as a tool to implement cardiometabolic dietary interventions. Disclaimer: The views expressed in this material are of the authors and do not reflect the official policy or position of the U.S. Government, the Department of Defense, the Department of the Air Force, or the University of the Pacific. The voluntary, fully informed consent of the subjects used in this research was obtained as required by 32 CFR 219 and DODI3216.02_AFI40-402, Protection of Human Subjects and Adherence to Ethical Standards in Air Force Supported Research.
Abstract 14991: Local Prolongation of Repolarization Prevents Post Myocardial Infarction Ventricular Tachycardia
Authors: Ryan Ohara, Veronique Meijborg, Pouya Jelvehgaran, Jeanne van der Waal, Gerard J Boink, Natalia Trayanova, Ruben Coronel, Bastiaan J Boukens
Journal: Circulation (2022)

Introduction: Reentry is the predominant mechanism underlying ventricular arrhythmias in chronic myocardial infarction patients. Reentry can be prevented by prolonging effective refractory period, thereby blocking reexcitation of recently activated tissue. This is currently achieved with systemically administered class III antiarrhythmic drugs. These therapies are limited by their risk of provoking ventricular arrhythmias by off-target effects. Hypothesis: Local prolongation of repolarization in healthy myocardium adjacent to the exit site attenuates reentry and postinfarction arrhythmias. Method and results: We used a pig model and generated myocardial infarction by balloon occlusion of the left anterior descending coronary artery and performed epicardial mapping 6 weeks later during Langendorff-perfusion. Programmed stimulation induced reentry leading to ventricular premature beats and sustained ventricular tachycardia (VT). Local injection of Sotalol adjacent to the infarcted myocardium prolonged repolarization and prevented VT after programmed stimulation. To translate these experimental findings to the patient situation we used a virtual heart based on data from a patient suffering from postmyocardial infarction VTs. The patient underwent pre-ablation cardiac late gadolinium enhanced- magnetic resonance imaging followed by geometrical reconstruction of the left ventricle and computational electrophysiological modelling of VT induction. We used a rapid pacing protocol to induce VT and determined the site where the activation front exited the infarct zone and reactivated the adjacent normal myocardium. Next, we prolonged repolarization of the normal myocardium adjacent to the exit site with 50 ms and performed rapid pacing to induce VT. This only resulted in a single premature ventricular beat after which sinus rhythm restored. Conclusion: Our experimental and in silico findings show the potential of local prolongation of repolarization a novel potentially genetic anti-arrhythmic therapy in post-infarction patients.
Abstract 15219: Optogenetic “Printing” of Reentrant Arrhythmias in Human Induced Pluripotent Stem Cell Derived Cardiac Tissues
Authors: Michal Landesberg, Yehuda Wexler, Gil Arbel, Irit Huber, Lior Gepstein
Journal: Circulation (2022)

Introduction: Current models used to investigate reentrant arrhythmias allow for limited control of arrhythmia parameters and morphology. Here, we developed a method for the induction of morphologically and physiologically defined arrhythmias using human induced pluripotent stem cell derived cardiac cell sheets (hiPSC-CCSs) and optogenetic tools. Methods: One million hiPSC-cardiomyocytes expressing the optogenetic channel CoChR were used to create the hiPSC-CCSs. Rotor illumination patterns were generated either by computer-aided design or by utilizing previously recorded rotor patterns. A digital micro mirror device (DMD) and a 470nm LED were used to project five complete cycles of these rotor patterns onto the hiPSC-CCSs. Results: Optical projection of typical rotors led to repeated development of arrhythmias in all sampled tissues (n=11). The resulting arrhythmias resembled the projected rotor patterns in terms of directionality (clockwise or counterclockwise) and number of cores ,and were highly reproducible for each projection (Fig.1A). Interestingly, we identified a minimal and maximal frequency of the projected rotor that could induce arrhythmias (Fig.1B). Moreover, the frequency of the generated rotor could not be increased beyond a certain value despite further increases in the projected rotor frequency (Fig.1B). Lastly, to assess the effects of tissue EP properties, the process was repeated after treatment with the IKr blocker E-4031 (30nM). E-4031 treatment significantly reduced the minimal and maximal frequencies of the projected rotor that could still induce arrhythmia and slowed the maximal frequency of the resulting rotor (Fig.1B). Conclusions: We present a new method for the optical induction of reentrant arrhythmias allowing the generation of rotors rapidly, reproducibly, and with a predesigned morphology. This approach may allow for a paradigm shift in the way reentrant arrhythmias are studied.